Photocatalytic C-F alkylation; Facile access to multifluorinated arenes

Article abstract of DOI:10.1039/c5sc03013g

C-F functionalizations that provide C-C bonds are challenging synthetic transformations, due in part to the large C-F bond strength, short bond length, nonpolarizable nature, the production of fluoride, and the regioselectivity-in the case of multifluorinated substrates. However, commercially available highly fluorinated arenes possess great synthetic potential because they already possess the C-F bonds in the desired locations that would be difficult to selectively fluorinate. In order to take advantage of this potential, selective C-F functionalizations must be developed. Herein, we disclose conditions for the photocatalytic reductive alkylation of highly fluorinated arenes with ubiquitous and unactivated alkenes. The mild reaction conditions provide for a broad functional group scope, and the reaction is remarkably efficient using just 0.25 mol% catalyst. Finally, we demonstrate the utility of the strategy by converting highly fluorinated arenes to elaborate (hetero)arenes that contain 2-5 C_aryl-F bonds via synergistic use of photocatalysis and S_NAr chemistry.

Full text of DOI:10.1039/c5sc03013g

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Photocatalytic C–F alkylation; facile access to
multifluorinated arenes†
Cite this: DOI: 10.1039/c5sc03013g
*
A. Singh, J. J. Kubik and J. D. Weaver
C–F functionalizations that provide C–C bonds are challenging synthetic transformations, due in part to the
large C–F bond strength, short bond length, nonpolarizable nature, the production of fluoride, and the
regioselectivity-in the case of multifluorinated substrates. However, commercially available highly
fluorinated arenes possess great synthetic potential because they already possess the C–F bonds in the
desired locations that would be difficult to selectively fluorinate. In order to take advantage of this
potential, selective C–F functionalizations must be developed. Herein, we disclose conditions for the
photocatalytic reductive alkylation of highly fluorinated arenes with ubiquitous and unactivated alkenes.
The mild reaction conditions provide for a broad functional group scope, and the reaction is remarkably
efficient using just 0.25 mol% catalyst. Finally, we demonstrate the utility of the strategy by converting
highly fluorinated arenes to elaborate (hetero)arenes that contain 2–5 Caryl–F bonds via synergistic use
of photocatalysis and SNAr chemistry.
Received 13th August 2015
Accepted 14th September 2015
DOI: 10.1039/c5sc03013g
www.rsc.org/chemicalscience
suited to provide access to multi-uorinated arenes, since this
would require the synthesis of unduly complicated starting
Introduction
materials.
Partially uorinated arenes make up an extremely important
class of molecules within the pharmaceutical1 and crop science2
industries. In 2013, the FDA approved 27 new small molecule
entities.3 Of these, 9 contain C–F bonds and 4 (Adempas, Gilo-
trif, Tanlar, Tivicay) contain aryl C–F bonds. Aryl uorides
share a similar importance in the crop protection sciences4 with
over 5.6 billion pounds of pesticides produced annually5 with
important aromatic uorides such as Teuthrin, Lufenuron,
Clodinafop and Saufenacil.6
An alternative approach to multiuorinated arenes, which
has been championed by others,10 is to use highly or per-
uorinated arenes, which provides the carbon framework with
Despite their simple appearance, synthesis of partially uo-
rinated molecules such as 1.1 (Scheme 1a) typically rely on
classic but lengthy uorination strategies. Synthesis of acid 1.1
involves the commonly employed nitration, halex, reduction,
Balz–Schiemann sequence. While the requisite acid (1.1) used
by Merck in the synthesis of Januvia is commercially available, it
requires seven steps to synthesize and highlights the need for
the development of new strategies to access multiuorinated
arenes. More recently, much effort has been focused on devel-
oping modern uorination strategies to facilitate discovery
efforts (Scheme 1b). C–H uorination7 strategies as well as more
traditional cross-coupling strategies using both nucleophilic8
and electrophilic9 uorine have recently been published.
Importantly, while these methods have provided numerous
methods to conduct selective uorination, they are not well
107 Physical Science, Department of Chemistry, Oklahoma State University, USA.
E-mail: Jimmie.Weaver@Okstate.Edu
Scheme 1 Synthesis of Januvia's fluorinated precursor and compar-
ison of strategies. a) currently employed strategy, b) potential selective
fluorination approaches, c) proposed strategy.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5sc03013g
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the desired uorine atoms already in place. The undesired compared to other sp3-hybridized coupling partners because
uorine atoms can then serve as functional group handles to they would require no prefunctionalization and, between
transform the molecule into the desired product. Thus, they can natural compounds and synthetic methods, would provide
effectively serve as synthetic linchpins and provide access to enormous substrate variety. Herein, we demonstrate the rst
uorinated molecules not previously possible or potentially photocatalytic C–F reductive alkylation and show that when
shorten the synthetic sequence to important molecules such as used synergistically with photocatalytic C–F reduction, and SNAr
1.1. Importantly, peruoroarenes are readily available by chemistry it is capable of rapidly delivering remarkably complex
exhaustive uorination or the halex process11 and many are multiuorinated arenes.
commercially available.
While at the outset, this strategy sounds conceptually
Results and discussion
Based on our previous work,23 we expect the reaction to take
straightforward, there are several signicant challenges asso-
ciated with this approach that have prevented it from being
implemented. Namely, C–F bonds are remarkably strong,12
place via electron transfer from the photocatalyst to the per-
short,13 and not signicantly polarizable14-making them both
uoroarene,24 which results in C–F fragmentation and gener-
kinetically and thermodynamically robust. Furthermore, even if
ates a uoride25 and a peruoroaryl radical. We hoped that this
the bond is broken and uoride formed, it oen forms strong
radical could be enticed to undergo C–C bond formation with
metal–F bonds which can lead to sluggish catalyst turnover,
an alkene rather than H-atom transfer. It is worth noting that
making metal-catalyzed processes difficult.15 Finally, if all these
issues are circumvented, the regioselectivity of the C–F func-
tionalization could still be problematic given that the arene
contains multiple C–F bonds.
Nonetheless, some progress has been made in the area of
selective C–F alkylation of highly uorinated arenes.10b,10c,16 For
instance, Li has demonstrated that magnesiates are sufficiently
most systems used for the generation of aryl radicals typically
begin with aryl iodides and bromides, are subject to rapid
secondary reduction to give an aryl anion. Consequently, these
reactions are typically limited to fast cyclizations26 which can
compete with reduction.27 We hoped that the undesirable over-
reduction could be avoided by using an amine reduction
system, which would allow the generation of a polyuoroaryl
nucleophilic to add uncatalyzed to peruorinated arenes.17 The
radical that could undergo productive C–C formation to give an
Love group has developed a benzyl imine directed Pt-catalyzed
alkyl radical. Finally, the alkyl radical would need to undergo a
alkylation reaction.16f,16g,16i More recently, Wu has shown that
controlled H-atom abstraction with the amine radical cation, or
phosphonium ylides are capable of undergoing C–F substitu-
tion.18 These methods are important examples of selective C–F
the amine,28 to provide the product without undergoing unde-
sired radical reactions such as dimerization or oxidation/
functionalization. However, there is still a pressing need for the
substitution. Thus, we set about developing the reductive
development of novel strategies to alkylate C–F bonds in order
to achieve the full synthetic potential of highly uorinated
alkylation of peruorinated arenes with alkenes.
arenes. Therefore, reactions that take place via mechanistically
distinct pathways and also provide access to complimentary
products are of signicant value.
Table 1 Optimization of reaction conditions
Others have shown that photocatalysis can be used to reduce
benzylic bromides,19 a-bromo-malonates, –ketones20 –chal-
cones,21 aryl-iodides and even a few activated aryl bromides.22 In
2014, we demonstrated that visible light photocatalysis could be
used to perform selective hydrodeuorination of per-
uoroarenes.23 This method proved ideal for avoiding many of
the challenges facing metal-catalyzed methods for C–F func-
tionalization. Specically, the catalyst, fac-Ir(ppy)3, is an 18-
electron complex that is tris-cyclometalated and coordinatively
saturated and provides little opportunity to form problematic
M–F bonds. The reaction was postulated to have taken place by
an electron transfer to the arene which typically resulted in a
selective C–F bond fragmentation event. Furthermore, the
method was mild and functional group tolerant. Thus, we were
eager to see if the intermediate could be utilized to form a C–C
bond (eqn 3, Scheme 1) which would help us realize our larger
goal of making peruoroarenes a useful synthetic linchpin by
providing complimentary reactivity to classic SNAr chemistry
common to (hetero)aryl uorides. We chose to initiate our
investigation with alkenes, which we hoped could serve as a
surrogate for an alkyl group by in situ reduction. From a
synthetic viewpoint, the use of alkenes was attractive when
Entry Modications
Conv.a 1a/1a0 Time
1
None
100% 2.6
8 h
2
No Ir(ppy)3, DIPEA, or light
0%
na
na
8 h
8 h
2 d
3
THF, DCM, or toluene instead of MeCN 0%
4
5
6
7
8
9
10
11
12
13
14
MeNO2, DMF instead of MeCN
DMSO instead of MeCN
1.2 equiv. cyclohexene
2.4 equiv. cyclohexene
3.6 equiv. cyclohexene
4.8 equiv. cyclohexene
6.0 equiv. cyclohexene
10.0 equiv. cyclohexene
Ir(ppy)3, (0.5 mol%)
100% nab
99%
73%
57%
59%
58%
68%
39%
72%
73%
35%
1.7
0.8
1.5
1.8
2.1
1.8
2.5
3.2
2.8
2.9
8 h
2.2 h
2.2 h
2.2 h
2.2 h
2.2 h
2.2 h
5.5 h
5.5 h
5.5 h
Ir(ppy)3, (0.25 mol%)
Ir(ppy)3, (0.125 mol%)
a
Determined by 19F NMR. b Unidentied products formed.
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Table 2 Scope of the C–F reductive alkylationa
Fig. 1 Conversiona as a function of catalyst normalized potential.b (a)
Determined by 19F NMR. (b) All potentials are given in V versus the
Standard Calomel Electrode (SCE). The Y-axis shows the relative
reducing or oxidizing potentials of the catalysts. (c) The ratio of 1a/1a0
varied only slightly 2.2–3.2.29
We began the optimization using pentauoropyridine and
cyclohexene (Table 1, entry 1). Starting with conditions that facil-
itated the photocatalytic hydrodeuorination23 (HDF) we screened
solvents (entry 3–5). When toluene, THF, or DCM were used as the
reaction solvent, no reaction occurred (entry 3). The use of nitro-
methane or dimethylformamide led to unidentied products.
While use of DMSO led to product formation, it gave a decrease in
the relative amount of alkylated (1a) to HDF product (1a0).
We next evaluated the effect of the concentration of the
alkene on the reaction outcome (entries 6–11). At low alkene
concentration the reaction proceeded noticeably faster, but gave
greater amounts of the HDF product. While high alkene
concentration (10 equivalents, entry 11) gave a moderately
greater product ratio, it proceeded more slowly. We ultimately
chose 6 equivalents of alkene as a compromise between the two
a
Yields correspond to isolated product. The regioisomeric ratio (rr) and
diastereomeric ratio (dr) with respect to the alkene were determined by
1H NMR of the crude reaction mixture aer workup.
extremes. Additionally, we investigated the concentration of the the product distribution (1a/1a0) were observed which is
photocatalyst (entries 12–14). We found that the loading could consistent with a C–C bond forming event which is independent
be dropped to 0.25 mol% before any effect on the yield was of the catalyst.
observed.
In contrast to our previous suggestion,23 careful inspection of
Next, we investigated the nature of the catalyst on both the these results indicate that electron transfer to the per-
selectivity and conversion of the reaction (Fig. 1). The catalyst uoroarene can mostly likely take place via either reductive or
we investigated ranged from strongly reducing excited states oxidative quenching cycles or potentially both simultaneously.
(E1/2(Ir+/Ir*), lane 3, Fig. 1), to strongly oxidizing excited states (E1/ For instance, Ir(ppy)3 and Cat A could proceed through an
2(Ir*/Irꢀ), lane 4). This makes them more prone to undergo oxidative quenching path,30 despite a slight underpotential
oxidative and reductive quenching of the photocatalyst, (C5F5N ꢀ2.17 vs. Ir(ppy)3 ꢀ 2.01 and Cat A ꢀ1.94, E1/2 vs. SCE).31
respectively.
While a reductive quenching of these photocatalysts by the
Previously, we proposed that the photocatalytic HDF took amine is possible (EtNiPr2 + 0.68 vs. 0.51 (Ir(ppy)3), 0.27 (Cat A),
place via reductive quenching to give the reduced Ir(II) species. E1/2 vs. SCE)32 this process is even more endothermic. The
It is from the reduced catalyst, Ir(ppy)3ꢀ, that electron transfer is photoexcited state of Cat B is less reducing (ꢀ1.70 V vs. SCE)
thermodynamically favourable. Interestingly, while the relative and less likely to undergo reductive quenching but is more
rates varied, the reaction proceeded with all the photocatalysts oxidizing (0.58 V vs. SCE) and still undergoes efficient coupling.
despite large differences in potentials. Only small changes to Furthermore, the reduced Cat Bꢀ is a strong reductant (ꢀ2.18 V
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Table 3 Trifluorinated arenes
Scheme 2 Exploiting fragmentation selectivity to access isomers.
Complex alkenes are available from synthetic methods and
nature and we were eager to see if they could be used to easily
incorporate alkyl groups that were not only functionally, but
also stereochemically dense. We found norbornene to be an
excellent substrate (15a) as well as the furan derived [4 + 2]
adduct (16a) which contains several sensitive functional groups
and base labile stereocenters.
vs. SCE), suggesting that when Cat B is used, a reductive
quenching event followed by electron transfer to the penta-
uoropyridine is the dominant path (Table 2).
Interestingly, Cat C, which could engage in a near thermo-
neutral electron transfer by undergoing reductive quenching
and then electron transfer, actually performs more modestly
than Cat B. While Cat D and Cat E for which reductive
quenching is almost certainly the primary mechanistic path,
Cat E outperforms Cat D despite an even more substantial
underpotential. This may be a result of the cationic nature of
Cat E which may electrostatically stabilize the incipient radical
anion formed from pentauoropyridine.33 Further complicating
the picture, Scaiano has demonstrated that if a-amino radicals
are generated they too can also serve as reductants, in some
instances.28 Given the relatively small difference observed in the
best performing photocatalysts, we opted to use the more
common Ir(ppy)3 catalyst. Thus, we began to explore the scope
of the reaction using N,N-diisopropylethylamine (DIPEA) (1.2
equiv.), alkene (6.0 equiv.), Ir(ppy)3 (0.25 mol%) in MeCN (0.1
M) with visible light irradiation with blue LED strips.
Initially, we looked at a series of peruoroarenes with
cyclohexene to evaluate the generality of the scope with regard
to arene. We found that moderate to good yields could be
obtained directly from a number of peruoroarenes including
pyridine (1a), benzonitrile (2a), thiocarbonate (3a), esters (4a),
heterocyclic substituted (5a), and even phosphine (6a). We were
concerned that the intermediate radical might be too reactive to
be selective, but we found that differences in the substitution
pattern of the alkenes led to excellent selectivity, with addition
occurring at the less substituted carbon (7a, 10a, 11a, 12a and
13a). The reaction proceeds smoothly in the presence of elec-
tron rich dihydropyran (8a) as well as with electron poor
cyclohexenone (9a) which gives a single regioisomer. 12a is
derived from 3-chloro tetrauoropyridine and demonstrates the
orthogonal reactivity of the photocatalytic functionalization and
SNAr chemistry which is selective for the 4-F in the per-
uoropyridine system. 12a is also noteworthy because no 5-exo-
trig cyclization product (a benzofuran derivative) is detected
and highlights the mild reaction conditions. Likewise, the
primary alkyl chloride is well tolerated (13a).34
Reaction with acrylates provides the saturated b-uoroary-
lated esters (18a–20a). Reaction with methyl cyclohexene
provides the trans-1,2-disubstituted cyclohexane with moderate
stereoinduction (21a, 5.7 : 1 dr). Decauorobiphenyl undergoes
a rapid second photocatalytic C–F fragmentation event and
allows facile access to the tandem reductive alkylation and HDF
product (17a) which can be further elaborated by traditional
methods that utilize the enhanced acidity of the Ar–H.35
We expected that the highly uorinated nature of the arenes
would facilitate elaboration of the structure by SNAr reactions.
However, it was not known how well the photocatalytic reaction
would work aer the uorines which also serve to activate the
arene towards electron addition were removed36 (E1/2 red C6H6 ¼
ꢀ3.42 vs. SCE37 and E1/2 red C6F6 ¼ ꢀ2.81 vs. SCE38). In other
words, we were concerned that substitution of the uorines
would make the photochemical reactions too sluggish to be
useful. Nonetheless, we next began to look at substrates in
which at least one uorine had already been used to synthesize
the desired substrate (Table 3). When the acetophenone derived
benzofuran was exposed to cyclohexene we obtained the tri-
uorinated, alkyl substituted 22a in good yield.
Triuoroarenes (23a, 25a), (24a, 26a) and 27a are derived
from octauorotoluene, methylpentauorobenzoate and pen-
tauoropyridine, respectively. When the 4-position is
substituted, the substrates undergo photocatalytic reductive
alkylation at the position ortho to the triuoromethyl group,
Scheme 3 Tandem addition and ring opening.
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Scheme 4 Perfluoroarenes as synthetic linchpins.
ester group, or nitrogen atom. When performed together these reasonable yields. In this case, the C–Cl bond is fragmented
two substitution manifolds provide rapid access to complex preferentially to the C–F bond. This highlights the synthetic
multi-uorinated arenes which contain diverse functional versatility and predictability of this approach.
groups such as aryl ethers, esters, amides and even amino acid
derivatives.
When vinyl cyclobutane a-pinene was used, an optically
active ring-opened trisubstituted cyclohexene was obtained
By taking advantage of the orthogonal nature of SNAr and the rather than the standard reductively alkylated product (30a,
photochemical functionalization, access to isomeric uoroar- Scheme 3). This likely results from peruoroaryl radical addi-
enes is possible.
tion to the less substituted terminus of the alkene followed by
The normal regioselectivity of the photocatalytic C–F frag- ring-opening and nally reduction exocyclic radical suggesting
mentation event can be overridden by utilizing the mono- that the ring-opening event occurs faster than the reduction of
chlorinated starting material which results in perfectly selective the tertiary radical (under these conditions).40 Furthermore, the
C–Cl fragmentation. For example, subjecting uoroarenes 28 highly regio- and diastereoselective addition product may
and 29 (ref. 39) to photocatalytic conditions we were able to provide a convenient method for accessing more complex
isolate complimentary regioisomers (28a and 29a, Scheme 2) in optically active molecules which contain uoroaryl groups.
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Finally, having explored the scope of the reaction we sought to
demonstrate that peruoroarenes possess signicant synthetic
potential to provide both access to multi-uorinated arenes and
simultaneously serve as synthetic linchpins that allow a high
level of structural complexity to be built directly from the core of
the uorinated molecule-a strategy that has been, to date, under
utilized. To demonstrate this strategy, we employed a simple and
general sequence of SNAr and elaboration, followed by photo-
catalytic reductive alkylation and nally photocatalytic hydro-
deuorination (HDF). This sequence provides access to a diverse
and elaborate set of multi-substituted, diuorinated arenes and
heteroarenes in reasonable yields, 39%–55% with excellent
regiocontrol and uorine content control starting from just a few
inexpensive polyuorinated arenes (Scheme 4).41
Conflict of interest
The authors declare a competing nancial interest in that they
hold a patent United States Serial no. 62/043,650 concerning the
structure and method for the Meldrum's acid adducts.
Acknowledgements
The research results discussed in this publication were made
possible in total or in part by funding through the award for
project number HR-14-072, from the Oklahoma Center for the
Advancement of Science and Technology, and by NSF (CHE-
1453891) and by OSU-startup funds. We thank KAT and JID for
help in editing the manuscript.
For instance, starting with pentauoropyridine (eqn 8,
Scheme 4) the Meldrum's acid adduct42 is formed and then
decomposed in the presence of the glycine ethyl ester$HCl salt
to afford the amide in high yield. The tetrauoropyridine
product is then sequentially subjected to photocatalytic reduc-
tive alkylation and HDF to arrive at 31a in 55% overall yield.
Using the 3-chlorotetrauoropyridine analogue allows synthesis
of the regioisomer (32a) in 44% yield. The ability to easily access
both isomers could potentially facilitate structural activity
relationship studies. The commercially available Meldrum's
acid adducts29 are a versatile functional group handle that can
quickly provide other motifs such as esters, which can undergo
similar sequences (33a). This sequence can be extended to other
peruoroarenes such as methyl pentauorobenzoate (eqn 11)
and octauorotoluene (eqn 12 and 13). Synthesis of 35a
required only 0.25 mol% Ir(ppy)3 to carry out both photo-
catalytic steps. At the completion of the alkylation step, the
excess alkene was removed from the reaction mixture by
vacuum. Upon addition of solvent, amine, light, and degassing,
the photocatalytic-HDF reaction began. In some cases a puri-
cation step is required to remove impurities before progressing,
in spite of this substantial amounts of material (36a) can be
obtained in this short synthetic sequence.
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